A clear understanding of the early changes which take place during carcinogenesis is fundamental to a rational attack on pancreatic cancer. An important focus of these early changes is the determination of the cell of origin of pancreatic adenocarcinoma. In addition, the interplay between different carcinogens not only with pancreatic tissue proper but also with other reacting elements such as lymphoid and phagocytic cells must be understood. In our studies on chemical induction of pancreatic carcinoma so far, we have established a set of conditions which may be experimentally manipulated to allow observation of different responses, by the pancreas, to different known carcinogens and to promise some definition of the cell(s) of origin of adenocarcinoma. Our results have indicated that early changes occur in acinar cells to give them the appearance of ductules. These changes possibly begin at about the time changes in the secretory profile have been observed by others. Acinar origin of tubular complexes would shift the focus of cellular transformation to include acinar cells as well as ductal cells. Immunohistochemical techniques will be used to determine if the tubular complexes which develop during chemical carcinogenesis contain pancreatic enzymes, which would serve as a marker of cells which were once actively secreting acinar cells. Injection and ultrastructural techniques will be used to verify the tubular, anastomosing arrangement of the normal pancreas and the similarity of the fetal pancreas with the differentiation accompanying chemical carcinogenesis. Mesotheliomas induced by dimethylbenz(a)anthracene will be compared with adenocarcinomas. The ability of multinucleated giant cells to metabolically activate benzo(a)pyrene will be determined.